Summary: Circadian rhythms are critically important, since they enable most organisms to cope with the physical and ecological changes occurring daily in their environment. Indeed, they time most bodily functions, from basic metabolism to behavior, so that they are synchronized and optimized with the time of day. Because of their profound impact on physiology and behavior, disruption of circadian rhythms seriously impact human health. Mood disorders are linked to defective synchronization of circadian rhythms, and specific cancers and gastro-intestinal diseases are more frequent in shift workers, for example. We are using the fruit fly Drosophila melanogaster to study the fundamental principles underlying circadian rhythms and their synchronization (entrainment) to the day/night cycle. Indeed, a clock that drifts out of phase because it cannot respond to environmental cues or because its pacemaker mechanism is defective would have no adaptive value and be detrimental to health. We are pursuing three major objectives, using the full power of Drosophila genetics, molecular biology and neurobiology. Our first goal is to elucidate the molecular mechanisms of circadian entrainment to light and temperature cycles, the two most important environmental cues. We will determine at the molecular level how circadian pacemakers receive and respond to photic and thermal inputs, and how they integrate them. Our second objective is to understand how the circadian neural network controlling rhythmic behaviors detects, responds and integrates various environmental cues. Indeed, in the brain, entrainment relies both on cell-autonomous molecular mechanisms and interactions between circadian neurons to synchronize circadian behaviors with the day/night cycle. Finally, our third objective is to understand how circadian rhythms are generated at the molecular level, with a particular interest in determining how the control of mRNA processing and translation contributes to circadian rhythms. There is indeed growing evidence that these regulatory steps of gene expression are critical for circadian rhythms. However, in contrast to circadian transcriptional and post-translational control, little is known about the mechanisms regulating circadian mRNA metabolism and translation. We expect our work to provide an integrative picture of the mechanisms generating, controlling and synchronizing circadian rhythms in fruit flies. Importantly, the basic mechanisms underlying circadian rhythms are remarkably well conserved in animals, from Drosophila to mammals. We therefore anticipate that our work will also prove important for our understanding of mammalian circadian rhythms, and might thus ultimately impact our ability to treat diseases associated with disrupted circadian clocks.